Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208)

  • J Med Chem. 2016 Oct 13;59(19):9255-9261. doi: 10.1021/acs.jmedchem.6b00420.
Rossella De Marco  1 ,  Andrea Bedini  2 ,  Santi Spampinato  2 ,  Lorenzo Cavina  1 ,  Edoardo Pirazzoli  1 ,  Luca Gentilucci  1
Affiliations
  • 1. Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
  • 2. Department of Pharmacy and Biotechnology, University of Bologna , Via Irnerio 48, 40126 Bologna, Italy.
PMID: 27607020 DOI: 10.1021/acs.jmedchem.6b00420
Abstract

Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging macrocycle size, giving the μ-agonist 9 or the δ-antagonist 10 characterized by low nanomolar affinity. In particular, the μ-agonist c[β-Ala-d-Pro-Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.